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| United States Patent |
5,244,663
|
|
Bruttmann
, et al.
|
September 14, 1993
|
Therapeutic method against allergy
Abstract
Allergens are contained in strictly controlled and reproducible amounts on
solid supports to provide a progressive release of the allergen
perlingually and sublingually. The compositions are prepared by dissolving
an allergen in a polar solvent to obtain a mother solution; preparing
dilutions of different predetermined concentrations; fractionating each of
the dilutions into sub-dilutions; and impregnating a pharmaceutically
acceptable solid support with each sub-dilution, each impregnation step
being followed by drying in forced, dried air at a temperature not greater
than 30.degree. C.; and applying a protective coating onto the
composition.
| Inventors:
|
Bruttmann; Georges (Grenoble, FR);
Pedrali; Patrick (Annecy, FR);
Robert; Serge (Braine la chateau, BE)
|
| Assignee:
|
Medibrevex (Grenoble, FR)
|
| Appl. No.:
|
654977 |
| Filed:
|
February 14, 1991 |
Foreign Application Priority Data
| Current U.S. Class: |
424/400; 424/275.1; 424/434; 424/435; 436/529; 436/823; 514/960; 530/329 |
| Intern'l Class: |
A61K 009/20; A61K 009/48; A61K 047/26 |
| Field of Search: |
424/91,88,400,434,435
530/329
436/823,529
514/960
|
References Cited
U.S. Patent Documents
| 4171299 | Oct., 1979 | Hamburger | 530/329.
|
| 4364938 | Dec., 1982 | Hoek | 424/88.
|
| 4642232 | Feb., 1987 | Yman | 424/19.
|
| 5080903 | Jan., 1992 | Ayache et al. | 424/433.
|
| Foreign Patent Documents |
| 2099698 | Dec., 1982 | GB.
| |
Primary Examiner: Page; Thurman K.
Assistant Examiner: Harrison; Robert H.
Attorney, Agent or Firm: Browdy and Neimark
Parent Case Text
This is a continuation-in-part of application Ser. No. 07/415,379, filed
Sep. 29, 1989, abandoned, which is a continuation of application Ser. No.
07/149,499, filed Jan. 28, 1988, abandoned.
Claims
We claim:
1. A dosage form for treating allergies comprising an effective amount of
an allergen in a solid carrier which disintegrates under the action of
saliva in less than five minutes wherein said solid carrier is a mixture
of saccharose and lactose.
2. The dosage form of claim 1 wherein said allergen is selected from the
group consisting of household dust, acarica, hymenoptera and pollen.
3. A method for treating a patient suffering from allergy, by desensitizing
said patient to at least one allergen causing said allergy, comprising
administering said allergen sublingually and perlingually to said patient
in a plurality of solid doses at progressively increasing concentrations
of said allergen at respectively subsequent periods of treatment, each
dose comprising a solid excipient which is a mixture saccharose and
lactose, each dose containing a progressively increasing quantity of
allergen;
providing in one package doses of said allergen ranging from a lower
concentration of allergen to a higher concentration of allergen;
providing to said patient several different packages of said doses,
respectively increasing to said patient the dosage of said allergen,
wherein the higher concentration of one package of lower dosages is less
than or equal to the lower concentration of the subsequent package of
higher dosage; and
administering to said patient said packages of increasing dosages over the
course of the treatment by placing each dose in solid form in the
sublingual cavity of said patient and dissolving the excipient to deliver
the allergen to said patient.
4. The method of claim 3 wherein the solid excipient is in the form of a
tablet.
5. The method of claim 3 wherein the solid excipient is in the form of
discrete particles contained in a capsule.
6. The method of claim 3 wherein each package contains, for at least one
concentration of allergen, more than one identical solid doses containing
the same quantity of allergen.
7. The method of claim 3 wherein each package comprises at least four
different doses of said allergen, said doses having quantities of said
allergen which increase by a fixed increment over the preceding dose.
8. The method of claim 3 wherein the concentration of the higher dose of a
package of higher dosage is a multiple of the concentration of the higher
dose of the preceding package of lower dosage.
9. A method according to claim 3, wherein so as to obtain the respectively
different solid doses of said allergen:
said allergen is dissolved or suspended into a polar solvent, so as to
obtain a mother solution having a reference concentration in said allergen
successive dilutions of said mother solutions are prepared so as to obtain
respectively different diluted solutions having respectively decreasing
controlled sub-concentrations in said allergen
for each respective diluted solution, sub-dilutions are prepared so as to
obtain respectively different sub-diluted solutions having respectively
decreasing controlled fractionated concentrations in said allergen
incorporating said different fractionated sub-dilutions into respectively
different lots of said solid excipient, so as to obtain said respectively
different solid doses of said allergen.
10. The method according to claim 9 wherein said sub-dilutions are
incorporated into said lots of said solid excipient by impregnation,
wherein said impregnation step is followed by drying in forced dried air
at a temperature not greater than 30.degree. C.
11. The method according to claim 9 wherein, after said solid excipient has
been impregnated with allergen, a solid coating is applied to said
impregnated solid excipient.
Description
FIELD OF THE INVENTION
The invention relates to a therapeutic method against allergy, consisting
in administering to the patient at subsequent or successive periods
respectively increasing doses of at least one allergen, so as to
desensitize same patient to this allergen.
BACKGROUND OF THE INVENTION
Several desensitizing techniques have already been proposed.
According to document GB-A-2 099 698 (Melillo), it has been proposed to
incorporate an allergen in small particles of some tenth microns of a
pharmaceutically acceptable, in particular non-allergenic per se, solid
excipient, for instance lactose; then these particles are encapsulated
into calibrated capsules, for instance gelatine capsules. These capsules
are intended and adapted for an administration only by inhalation, either
by an inhaler tube or a nasal spray. This is the nasal way of
administration of an allergen.
This way of administration has the following drawbacks:
the quantity of the allergen actually transferred to the target organ, e.g
the lungs cannot be precisely controlled
it remains a cumbersome method requiring a fixed inhalation apparatus, and
thus cannot be an ambulatory treatment.
According to document EP-A-0 135 022 (MORAN), it has been proposed to
incorporate an allergen into particles of a solid excipient consisting of
an acid insoluble polymer. Such a solid dispersion of the allergen is
intended only for an oral administration to the target organ or cells,
through the gastro-enteric path.
This way of administration of an allergen suffers from the following
drawbacks:
it is mandatory to use very high concentrations of the allergen, since a
relatively important part of the latter is destroyed in the gastro-enteric
path
such concentrations may result in adverse side effects, such as
gastro-intestinal upsets
finally, it cannot be determined or controlled what is the amount actually
absorbed of the antigen, and thus it is difficult to establish an exact
dosage of the latter.
Further, stress has been given to the interest that a sublingual
application can offer (Glenis, K. et al, Clinical Allergy, 1986, Vol. 16,
483-491) which would make it possible to avoid certain secondary effects
of administration of the allergen by injection.
However, the galenic form selected (liquid form) is not entirely
satisfactory; when relatively large dosages (i.e., volumes) are reached, a
certain part of the liquid is absorbed orally and therefore escapes
sublingual application, which make it impossible to control all the
treatment factors. Therefore, this is a galenic form assuring very
approximate dosages.
However, this method of administration sublingually seems very promising
because the salivary IgA should play an important role in the
effectiveness of the treatment. The mechanism of desensitizing
sublingually, moreover, is approximately the same as that of desensitizing
by injection.
SUMMARY OF THE INVENTION
The inventors therefore have devoted all their efforts to studying a new
method for administering allergens, making it possible to benefit from all
the advantages of the mode of administration perlingually and
sublingually, but without having the drawbacks mentioned above.
They were able to develop a desensitizing method, ensuring a progressive
and rigorous dosage of the allergen, which therefore makes it possible to
assure a rigorous monitoring of the treatment. Further, the inventors were
able to determine, which is quite surprising, that this new therapeutic
method for application perlingually and sublingually makes it possible to
obtain a much faster desensitizing than that which can be obtained by
using other known ways of administration of allergens, whether it is
administration by injection, orally, or perlingually with an excipient or
support that is a liquid.
The therapeutic method according to the invention comprises:
obtaining respectively different solid doses of said allergen, each dose
comprising a pharmaceutically acceptable excipient in solid form
formulated so as to be disintegrated in less than 5 minutes in the
sublingual cavity under the action of saliva, and a controlled
fractionated quantity in said allergen, said doses being identical to one
another by the excipient, but differing respectively from one another by
their fractionated quantities in said allergen
conditioning in a same package respectively different solid doses of said
allergen, ranging progressively by their respective contents in said
allergen from a lower concentration in said allergen to a higher
concentration in the latter
providing several different packages of said solid doses, respectively
increasing the dosage in said allergen, the higher concentration of one
package of lower dosage being below or equal to the lower concentration of
the following package of higher dosage
administering said packages of increasing dosages, at respectively
subsequent periods of the treatment, by placing each dose in solid form in
the sublingual cavity, and then spitting out, the saliva having dissolved
in same cavity the excipient with said allergen.
With respect to the excipient in solid form, its components, their
concentrations and physical state, and the way of admixing them, are
choosen according to the usual practice of the pharmacologist, so as to
obtain a disintegration time of less than 5 minutes, preferably 2 to 3
minutes, in the environment and conditions of the sublingual cavity.
This invention is also characterized by the following auxiliary features.
The excipient in solid form may be a calibrated tablet or discrete
particles, such as grains, contained in a calibrated capsule.
Each package of a given dosage of said allergen contains for at least one
concentration of said allergen, several, for instance four identical solid
doses having the same corresponding fractionated quantity in said
allergen.
Each package comprises at least four different concentrations of said
allergen, that is at least four different solid doses of said allergen,
having fractionated quantities of said allergen respectively increasing by
a fixed concentration increment, for instance 1/4 of a given
concentration, over the precedent.
The different packages bring respectively overall increasing dosages of
said allergen. To this end, the concentration of the higher solid dose of
a package of higher dosage is a multiple, for instance by ten, of the
concentration of the higher solid dose of the precedent package of lower
dosage.
So as to obtain the respectively different solid doses of said allergen:
said allergen is dissolved or suspended into a solvent, so as to obtain a
mother solution having a reference concentration in said allergen
successive dilutions of said mother solutions are prepared so as to obtain
respectively different diluted solutions having respectively decreasing
controlled sub-concentrations in said allergen
for each respective diluted solution, sub-dilutions are prepared so as to
obtain respectively different sub-diluted solutions having respectively
decreasing controlled fractionated concentrations in said allergen
incorporating said different fractionated sub-dilutions into respectively
different lots of said solid excipient, so as to obtain said respectively
different solid doses of said allergen.
The fractionated sub-dilutions are incorporated into respectively separate
lots of said excipient in solid form, for instance a mixture of saccharose
and lactose, by a multi-impregnation or fractionated impregnation, each
impregnation step being followed by drying, in forced dried air at a
temperature not greater than 30.degree. C. Preferentially, a protective
coating is applied to the excipient in solid form, after the impregnation
with each said fractionated sub-dilution.
Thus, as far as a desensitizing treatment is concerned, the invention
brings a novel way for the allergen of acceding to the sublingual cavity,
in progressive and controlled quantities. This way which may be named the
solid way brings the following basic advantages:
the therapeutic treatment may be effected with no stress or medical help
once the solid excipient has been disintegrated it leaves a precise
quantity of the allergen within the mouth, without any action or
manipulation of the patient
once prepared, no solvent or extraneous matter remains on the particles or
tablets of allergen
the patient may control and monitor his treatment himself, in cooperation
with his physician.
This method according to the invention has also brought some specific
pharmaceutical effects, for some allergens, which dispensed by other
methods do not exhibit such effects. These effects are mainly:
generally speaking, no adverse reaction
accelerated or faster clinical action
one reproducible and effective transfer to the blood, for a predetermined
dose of the allergen.
DETAILED DESCRIPTION OF THE INVENTION
The method for obtaining the solid forms of allergens according to the
invention will now be described in detail.
The starting product is a lyophilized allergen. This allergen can be of any
type: household dust, acarica, hymenoptera, pollen of Graminaceae or
other, whether they are pneumallergens or microbial or food allergens.
The lyophilized allergen is put in solution in any suitable solvent to
obtain a mother solution at 100 IR (index of reaction). The solvent used
can be water or physiological serum; it can also be selected from other
solvents, preferably polar solvents, such as low strength ethyl alcohol.
By IR or index of reaction is meant a measure of the quantity of the
allergen in a solvent or in solid form, or on a solid support, obtained as
follows:
an extract of said allergen is standardized as a reference quantity by in
vivo tests made on a population of thirty patients who have proved to be
allergic to same allergen; this reference quantity is the quantity of said
allergen which, once inoculated by a trans-epidermal injection on the
anterior face of one fore-arm, induces where injected a papula having the
same dimensions as the papula induced in the same way by a titrated
solution of codeine phosphate, having a weight concentration of 9%
then the various samples of same allergen are titrated versus this
reference quantity by the so-called RAST-inhibition technique (see method
of Yman L. and coll., Develop. Biol. Standard., Karger Basel, Vol. 29,
pages 151-165, 1975)
when the activity of the sample, titrated by above method is the same as
the reference quantity, then its index of reactivity is 100 IR.
Then, using the same solvent as that which served to obtain the mother
solution, successive dilutions at 10 IR, 1 IR, 0.1 IR, 0.001 IR and 0.0001
IR are obtained.
Each of these diluted solutions is then fractionated into different
sub-diluted solutions having respectively decreasing fractionated
concentrations in the allergen. For instance, the diluted solution at
0.001 IR is fractionated into sub-diluted solutions having concentrations
of respectively 1/4.times.0.001 IR, 2/4.times.0.001 IR, 3/4.times.0.001
IR, while keeping a solution of 4/4.times.0.001 IR. The sub-diluted
solutions may represent another fraction, for instance a multiple of 1/15
of the concentration of the starting diluted solution.
All the precautions will be taken, during each of the dilutions or
sub-dilutions, so that the amount of solvent remains constant, to perform
later all impregnation of the solid excipient in an identical way.
All the so-obtained different fractionated sub-dilutions, or a calibrated
portion thereof, are incorporated into respectively different lots of a
same solid excipient, for instance a mixture of saccharose-lactose, in the
form of globules, but the latter may be replaced by powders or tablets.
The lots are different in that they are devoted respectively to different
dilutions and sub-dilutions, but they are composed of the same quantity in
divided form of the same excipient.
Each lot is impregnated with a given dilution, or sub-dilution, in a manner
known per se, for instance with a "spray doser" injector.
Thus, the technique of impregnation is that of multi-impregnation or
fractionated impregnation to guarantee a perfect distribution of the
homogeneous allergen of the various globules of the excipient.
Between each impregnation, drying is performed by passing of forced, dried
air into a chamber where low pressure prevails obtained by the difference
of flow existing between this air passage and a powerful extractor.
According to an important characteristic of the invention, this drying
operation is performed at a temperature not greater than 30.degree. C. It
has been determined during numerous tests performed for development of
said process, that this process is no longer reliable when the temperature
exceeds 38.degree.-40.degree. C.
The last impregnation is a protective impregnation which forms a protective
coating on the granules of the solid excipient.
According to another embodiment of the process according to the invention,
and to guarantee that the physiochemical integrity of the allergen is
totally maintained, the various impregnation steps are performed under a
nitrogen atmosphere.
The final operation consists in putting the globules thus obtained into
capsules, or optionally in placing said globules or powders or tablets in
elementary tubes and in completing the packaging in a standard way
(blisters for the capsules, boxes for the tubes), numbering the capsules
with increasing doses.
Thus the following pharmaceutical presentation of the allergen may be
obtained:
the solid doses of the allergen obtained as above, i.e. calibrated
quantities of impregnayed granules contained in capsules, are distributed
in five packages, for instance calender plates, according to their
fractionated quantities in same allergen
these packages represent increasing dosages of said allergen, for instance
0.001 IR, 0.01 IR, 0.1 IR, 1 IR, and 10 IR
on each package is numbered in increasing order, for instance 1 to 16,
individual casings for receiving capsules of increasing fractionated
quantity in said allergen; for instance, for the package of 0.001 IR
dosage, the casings 1 to 4 are allotted to the fractionated quantity
1/4.times.0.001 IR, 5 to 8 to the fractionated quantity 2/4.times.0.001
IR, 9 to 12 to the fractionated quantity 3/4.times.0.001 IR, and 13 to 16
to the quantity 0.001 IR
and the higher concentration of one package of lower dosage, for instance
0.001 IR, is below the concentration of the following package of higher
dosage, for instance 1/4.times.0.01 IR.
With the pharmaceutical presentation, the allergen may be administered
progressively, over a period ranging from forty to fifty days. For
instance, during five weeks, the patient takes respectively the five
packages of increasing dosage, and has four doses a day for the same
fractionated quantity. For each dosage, the patient places the content of
one capsule in the sublingual cavity, without swallowing; after complete
disintegration of the solid excipient, for instance in less than 3
minutes, he then spits out his saliva having dissolved in the sublingual
cavity the excipient with the allergen.
After such a treatment, the patient may take so-called stabilization doses,
with one dose per day, then twice a week, then once a week.
It has been found that, in a very surprising way, relative to standard
desensitizing and particularly relative to desensitizing by injection, the
clinical results are very much superior; and 80 to 85% improvement is
noted at the end of two to three months of treatment. The production of
antibodies of the IgG4 type is accelerated and the tolerance is perfect.
Only 2 to 3% of syndromic reactions have been counted; these are easily
controlled by reduction or spacing of taking the doses.
Another entirely surprising advantage of the therapeutic method according
to the invention is that the desensitizing period is very greatly reduced
relative to other known methods. The treatment no longer lasts several
years but simply some months, and especially, it is possible to attain
maximum doses very rapidly, between eighty and one hundred days.
The new galenic forms of allergens according to the invention offer still
other advantages, among which can be cited a considerable reduction of the
densitizing cost, considering the almost disappearance of medical
consultations or nurses' care. Only checking consulations in a month or
two are necessary.
Double blind tests made against a placebo on more than two thousand
patients confirms the above.
The experimental results are shown as follows:
______________________________________
ACARICA
Results of Sublingual Desensitization of Adult Annual
Rhinitis
Very No
Patients
Good Good Fair Effect
Results
______________________________________
Active 13/15
allergen
15 9 1 3 2 86%
Placebo 1/15
15 0 1 0 14 6.5%
______________________________________
______________________________________
POLLEN OF GRAMINACEAE
Results of Pre-Season Sublingual Desensitization
(30 Pollens)
Very No
Patients
Good Good Fair Effect
Results
______________________________________
Active 12/15
allergen
15 9 3 0 3 80%
Placebo 2/15
15 0 0 2 13 13%
______________________________________
______________________________________
ACARICA
Results of Annual Sublingual Desensitization of
60 Alleragic Asthmatics
Very No
Patients
Good Good Fair Effect
Results
______________________________________
Active 23/29
allergen
29 9 11 3 6 75%
(1 dropped
out of
study)
Placebo 6/28
28 1 3 2 22 21.5%
(2 dropped
out of
study)
______________________________________
It is quite evident that this invention is no limited to the
concentrations, modes of fractionating or dilutions given above by way of
nonlimiting example; these concentrations, modes of fractionating and
dilutions can, of course, be adapted on demand; also the
saccharose-lactose support can be replaced by another pharmaceutically
acceptable support or excipient.
While the invention is described above in relation to certain specific
embodiments, it will be understood that many variations are possible, and
that alternative materials and reagents can be used without departing from
the invention. In some cases such variations and substitutions may require
some experimentation, but such will only involve routine testing.
The foregoing description of the specific embodiments will so fully reveal
the general nature of the invention that others can, by applying current
knowledge, readily modify and/or adapt for various applications such
specific embodiments without departing from the generic concept, and
therefore such adaptations and modifications are intended to be
comprehended within the meaning and range of equivalents of the disclosed
embodiments. It is to be understood that the phraseology or terminology
herein is for the purpose of description and not of limitation.
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